Method of manufacturing and testing solid dosage products and apparatus for the testing

Abstract

A method of manufacturing a solid dosage product includes the controlling of a measure of each of at least one property of dissolution of an ingredient of a sample of the solid dosage product, the measure of each of said at least one property being in an advantageous form and/or controlled in an advantageous manner, e.g., as a function of cumulative mass of the ingredient dissolved from the solid dosage product, and/or as determined under a member of certain advantageous dissolution conditions. A method of testing includes the determining and the evaluating of the measure of each of the at least one property in the advantageous form and/or in an advantageous manner. A dissolution testing cell includes features of construction advantageous for the determining A dissolution testing apparatus includes features of construction and combination of parts and components advantageous for use with the cell in the determining

1 - 25 . (canceled) 
     
     
         26 . A method of manufacturing a solid dosage product, comprising the controlling of a measure of each of at least one property comprising a property selected from the group consisting of:
 as a function of, at least, a measure of cumulative mass of an ingredient dissolved from a sample of the solid dosage product,
 (a.) differential rate of dissolution of the ingredient; 
 (b.) hydraulic conductivity of a particulate or bed of particulates of the sample; and 
 (c.) vertical velocity of fluidization of a particulate or particulates of the sample; and over given values of the, at least, a measure of cumulative mass, 
 (d.) mean value of a linear measure of the differential rate; 
 (e.) mean value of a linear measure of the hydraulic conductivity; and 
 (f.) mean value of a measure of the vertical velocity of fluidization; 
   wherein, each of said function and said linear measures is as empirically determined   
     
     
         27 . The method of  claim 26 , with reference to the selected property, the at least a measure of cumulative mass consisting of the measure of cumulative mass. 
     
     
         28 . The method of  claim 26 , with reference to the selected property, the at least a measure of cumulative mass consisting of the measure of cumulative mass and a measure of an independently variable dissolution medium contact time. 
     
     
         29 . The method of  claim 26 , the selected property being the (a.) differential rate or the (d.) mean value, the measure of (a.) or the linear measure, respectively, being as determined under each of one or more given dissolution conditions, at least a member of the one or more given dissolution conditions being selected from the group consisting of: (A.) discrete fluidization and settlement hydrodynamic condition of a known or calibrated linear vertical distance of local dissolution medium flow per cycle or per unit time; (B.) pressure sensitive packed bed hydrodynamic dissolution condition under a known or calibrated head pressure; (C.) dissolution condition repetitively occurring at first named time points or in first named time periods throughout a dissolution process, among time points or periods of another or other dissolution conditions different from dissolution condition of the first named time points or periods; and (D.) cyclic dissolution condition of an in vitro dissolution process each cycle thereof consisting of a time-series of dissolution conditions each thereof simulating a component dissolution condition of an in vivo dissolution process for a relative duration to length of cycle reflecting probability of occurrence of the component dissolution condition at a point of time in the in vivo dissolution process equal to a point of time of the cycle in the in vitro dissolution process. 
     
     
         30 . The method of  claim 26 , the selected property being the (a.) differential rate, the measure thereof being a member selected from the group consisting of: (A.) mass of the ingredient dissolved per unit linear vertical distance of local dissolution medium flow of a discrete fluidization and settlement hydrodynamic dissolution condition; (B.) mass of the ingredient dissolved per unit linear vertical distance of settlement of a discrete settlement hydrodynamic dissolution condition; (C.) mass of the ingredient dissolved per unit linear distance of local dissolution medium flow of a fixed position hydrodynamic dissolution condition; (D.) mass of the ingredient dissolved per unit linear distance of dissolution medium flow through a packed bed of a pressure-sensitive packed bed hydrodynamic dissolution condition; (E.) mass of the ingredient dissolved per unit time or per cycle of a cyclic dissolution condition; and (F.) any other measure of the (a.) obtained by the scaling of the (a.) with a factor chosen according to one or both of an in vivo dissolution condition and a simulative in vitro dissolution condition. 
     
     
         31 . The method of  claim 26 , the selected property being the (b.) hydraulic conductivity, the measure thereof being a member selected from the group consisting of: (A.) specific hydraulic conductivity to a dissolution medium; (B.) specific hydraulic resistance to a dissolution medium; and (C.) any other measure of the (b.) obtained by the scaling of the (b.) with a factor chosen according to one or both of an in vivo dissolution condition and a simulative in vitro dissolution condition. 
     
     
         32 . The method of  claim 26 , the selected property being the (c.) vertical velocity of fluidization, the measure thereof being a member selected from the group consisting of: (A.) terminal vertical velocity of settlement in a hydrostatic column of a dissolution medium; (B.) time taken to settle through a given vertical distance in a hydrostatic column of a dissolution medium, starting from a given initial vertical velocity of settlement; (C.) vertical distance of settlement through a hydrostatic column of a dissolution medium in a given amount of time, starting from a given initial vertical velocity of settlement; and (D.) vertical velocity of fluidization calibrated or computed from the member (B.) or from the member (C.). 
     
     
         33 . The method of  claim 26 , the selected property being the (d.) mean value, the measure thereof being a member selected from the group consisting of: (A.) mean mass of the ingredient dissolved per unit linear vertical distance of local dissolution medium flow of a discrete fluidization and settlement hydrodynamic dissolution condition; (B.) mean mass of the ingredient dissolved per unit linear vertical distance of settlement of a discrete settlement hydrodynamic dissolution condition; (C.) mean mass of the ingredient dissolved per unit linear distance of local dissolution medium flow of a fixed position hydrodynamic dissolution condition; (D.) mean mass of the ingredient dissolved per unit linear distance of dissolution medium flow through a packed bed of a pressure-sensitive packed bed hydrodynamic dissolution condition; (E.) mean mass of the ingredient dissolved per unit time or per cycle of a cyclic dissolution condition; and (F.) mean value of any other linear measure of the differential rate obtained by the linear scaling of the differential rate with a factor chosen according to one or both of an in vivo dissolution condition and a simulative in vitro dissolution condition. 
     
     
         34 . The method of  claim 26 , the selected property being the (d.) mean value, the given values of the, at least, a measure of cumulative mass consisting of a continuous, given interval of the measure of cumulative mass, the measure of (d.) being a member selected from the group consisting of:
 (A.) AUrMC, defined as ∫ A   B r(M)·dM, where the pair of values A and B denotes boundaries of the given interval, and the r(M) the linear measure expressed as a function of the measure of cumulative mass; (B.) mean differential rate over mass, defined as AUrMC/(B−A); (C.) mean dissolution time, defined as (B−A)/AUrMC; and (D.) any of the members (A.) to (C.) scaled with a factor chosen according to one or both of an in vivo dissolution condition and a simulative in vitro dissolution condition; wherein, preferably, each value of the linear measure at a given value of the measure of cumulative mass is as determined at a dissolution medium contact time effectively equal to time of an in vivo dissolution process at which time the measure of cumulative mass dissolved from a sample of the solid dosage product in the in vivo process is at said given value.   
     
     
         35 . The method of  claim 26 , the selected property being the (a.), the (b.) or the (c.), the at least a measure of cumulative mass consisting of the measure of cumulative mass, each value of the measure of the selected property, at a given value of the measure of cumulative mass in the function for the selected property, being as determined at a dissolution medium contact time effectively equal to a dissolution time of an in vivo dissolution process at which dissolution time the measure of cumulative mass of the ingredient dissolved from a sample of the solid dosage product in the in vivo dissolution process is at said given value. 
     
     
         36 . The method of  claim 26 , the selected property being the (a.), the (b.) or the (c.), value of the measure of the selected property, at each of a plurality of given values of the, at least, a measure of cumulative mass in the function for the selected property, being an average of values of the measure of the selected property, the average being as determined over replicates of the sample of the solid dosage product each at a same given value of the measure of cumulative mass dissolved therefrom. 
     
     
         37 . The method of  claim 26 , the selected property being the (a.), the (b.) or the (c.); the controlling comprising the determining and the evaluating of the measure of the selected property;
 the evaluating comprising the comparing of result of the determining to a specification on both an average of the measure of the selected property and variability of the average, at each of a plurality of given values of the, at least, a measure of cumulative mass; the controlling comprising the causing or ensuring of the measure of the selected property to meet said specification; and, said average and said variability being as determined over replicates of the sample of the solid dosage product each at a same given value of the measure of cumulative mass dissolved therefrom.   
     
     
         38 . The method of  claim 26 , the selected property being the (d.), the (e.) or the (f.); the controlling comprising the determining and the evaluating of the measure of the selected property; the evaluating comprising the comparing of result of the determining to a specification on both an average of the measure of the selected property and variability of the average; the controlling comprising the causing or ensuring of the measure of the selected property to meet said specification; and, said average and said variability being as determined over replicates of the sample of the solid dosage product each over said given values. 
     
     
         39 . The method of  claim 26 , the selected property being the (a.) differential rate; the controlling comprising the determining and the evaluating of the measure of the selected property; the evaluating comprising the comparing of output of a computational simulation with a specification on the output, input to the computational simulation comprising result of the determining either as is or after a mathematical manipulation; and, the controlling comprising the causing or ensuring of said output to meet said specification. 
     
     
         40 . The method of  claim 26 , the controlling comprising:
 monitoring a measure of one or more members selected from a group consisting of: (A.) attribute or composition of a raw material used in production of the solid dosage product; (B.) process variable in production thereof; and (C.) property of an intermediate product thereof; and   making a manufacturing decision based on result of the monitoring and a validated physical relationship between the measure of one or more members and the measure of the selected property.   
     
     
         41 . The method of  claim 26 , the selected property being the (a.) differential rate or the (d.) mean value; the measure of (a.) or the linear measure, respectively, being as determined under each of one or more given dissolution conditions at least a member thereof comprising a hydrodynamic dissolution condition which subjects a sample of the solid dosage product to dissolution in a fluidized state;
 either at least another member of the one or more given dissolution conditions comprising another hydrodynamic dissolution condition which subjects a sample of the solid dosage product to dissolution in a settled state, or the at least one property further comprising the (b.) hydraulic conductivity or the (e.) mean value.   
     
     
         42 . The method of  claim 26 , the at least one property comprising either or both of the (a.) differential rate and the (d.) mean value, and further comprising either or both of the (c.) vertical velocity and the (f.) mean value. 
     
     
         43 . The method of  claim 26 , the at least one property comprising either or both of the (b.) hydraulic conductivity and the (e.) mean value. 
     
     
         44 . The method of  claim 36 , the replicates of the sample each further having a dissolution medium contact time effectively equal to a dissolution time of an in vivo dissolution process at which dissolution time the measure of cumulative mass of the ingredient dissolved from a sample of the solid dosage product in the in vivo dissolution process is at said same given value. 
     
     
         45 . The method of  claim 36 , the selected property being the (a.), the determining being further under a same given homogenous or pseudo-homogenous physicochemical and hydrodynamic dissolution condition. 
     
     
         46 . The method of  claim 36 , the selected property being the (a.), the determining being further under a same given physicochemical dissolution condition and each of several different fundamental hydrodynamic dissolution conditions, said average being a weighted average, and a weight therefor reflecting the probability of a sample of the solid dosage product dissolving under a member of the several different fundamental hydrodynamic dissolution conditions at a point of time in an in vivo dissolution process at which point of time the measure of cumulative mass of the ingredient dissolved therefrom is at said same given value. 
     
     
         47 . A method of testing a solid dosage product, comprising the determining and the evaluating of a measure of each of at least one property comprising a property selected from the group consisting of:
 as a function of, at least, a measure of cumulative mass of an ingredient dissolved from a sample of the solid dosage product,
 (a.) differential rate of dissolution of the ingredient; 
 (b.) hydraulic conductivity of a particulate or bed of particulates of the sample; and 
 (c.) vertical velocity of fluidization of a particulate or particulates of the sample; and over given values of the, at least, a measure of cumulative mass, 
 (d.) mean value of a linear measure of the differential rate; 
 (e.) mean value of a linear measure of the hydraulic conductivity; and 
 (f.) mean value of a measure of the vertical velocity of fluidization; 
   wherein, each of said function and said linear measures is as empirically determined   
     
     
         48 . A dissolution testing cell comprising: a cell cavity and at least one opening thereto selected from the group consisting of: (a.) tangential opening, disposed either on a side wall of an axially symmetrical section of the cell cavity or in a peripheral portion of an end wall of the axially symmetrical section, oriented to a given circular direction and in fluid communication with a fluid connection port of the cell; and (b.) ring-shaped opening, disposed on side wall of the cell cavity away from ends thereof and fitted with a ring-shaped filter inner side thereof forming a part of the side wall, and outer side thereof being in fluid communication with a fluid connection port of the cell. 
     
     
         49 . A dissolution testing apparatus comprising: (a.) first pump means driving a stream of dissolution medium at a controlled or programmed flow rate; (b.) second pump means withdrawing a sample from a liquid or driving a sample out of a liquid; (c.) cumulative vessel storing a solute dissolved in a dissolution medium exited from a dissolution testing cell during a dissolution test; (d.) detection means either detecting a solute dissolved in a dissolution medium or providing a sample for the detecting; (e.) first switching valve means switching among at least two positions comprising first position and second position, the first position allowing a sample from the dissolution testing cell to travel to the detection means via a fluid conduit, under aid from either one or both of the first and the second pump means, and the second position a sample from the cumulative vessel; and (f.) control means controlling at least the independent functioning of the first and the second pump means, and the functioning of the first switching valve means.